NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
基本信息
- 批准号:10346091
- 负责人:
- 金额:$ 4.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-22 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Summary
Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC), but all
patients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent on
androgen receptor (AR) signaling, but a significant fraction lack AR expression, become AR signaling
independent, and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of these NEPC
variants has increased as more patients benefit from improved ADTs like enzalutamide and abiraterone acetate.
This suggests increasingly stringent AR signaling blockade is driving development of NEPC. NEPC is aggressive
and lethal, thus reflecting a growing clinical problem. Development of effective therapies is hampered by limited
understanding of relevant molecular mechanisms. NEPC clearly arises from ARpos CRPC as they share clonal
origin in patients that harbor both. We have determined that genetic inactivation of the RB1/TRP53 tumor
suppressor genes cooperate to facilitate transformation of ARpos PADC to NEPC through derepression of
epigenetic reprogramming factors. Inhibiting these reprogramming factors reverses NEPC transformation and
restores ADT sensitivity, demonstrating that epigenetic changes are involved. We hypothesize Notch signaling
within the tumor microenvironment suppresses the epigenetic reprogramming underlying NEPC
transdifferentiation. This hypothesis has clinical ramifications as the pathway could conceivably be
manipulated therapeutically to delay or reverse NEPC transformation, extending the duration of beneficial ADT
clinical responses in some patients. This administrative diversity supplement application is proposed to support
Mauricio Flores, a predoctoral student who will be involved in the parent R01 grant supported research program
characterizing the role of NOTCH signaling in NEPC transdifferentiation. The research, mentoring, and career
development plan proposes three research aims: 1) Identify organoid culture conditions sufficient to support
NEPC transdifferentiation in vitro; 2) Test how Notch signaling affects NEPC transdifferentiation in vitro; 3)
Identify stromal-cancer cell interactions that influence NEPC transdifferentiation in vitro. The long-term goal of
this diversity supplement is to facilitate Mr. Flores' cancer research career development and to improve prostate
cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired
therapeutic resistance.
概括
雄激素剥夺疗法(ADT)在治疗转移性前列腺腺癌(PADC)方面有效,但所有
患者不可避免地会因castrate抗性前列腺癌(CRPC)复发。大多数CRPC仍取决于
雄激素受体(AR)信号传导,但明显的部分缺乏AR表达,成为AR信号传导
独立和异常表达神经内分泌谱系标记(NEPC)。这些NEPC的发生率
随着越来越多的患者受益于enzalutamide和Abiraterone乙酸盐,变体的增加。
这表明越来越严格的AR信号阻塞正在推动NEPC的发展。 NEPC是积极的
和致命,因此反映了日益增长的临床问题。有限的有效疗法的开发受到阻碍
了解相关的分子机制。 NEPC显然是由ARPOS CRPC共享克隆的
起源于携带两者的患者。我们已经确定RB1/TRP53肿瘤的遗传失活
抑制基因合作以促进ARPOS PADC转化为NEPC
表观遗传重编程因子。抑制这些重编程因素逆转NEPC的转换和
恢复ADT敏感性,表明涉及表观遗传变化。我们假设Notch信号传导
在肿瘤微环境中,抑制了NEPC的表观遗传重编程
转变。该假设具有临床影响,因为可以想象的途径是
通过治疗操作以延迟或逆转NEPC转换,延长了有益ADT的持续时间
某些患者的临床反应。提出了这种行政多样性补充申请来支持
毛里西奥·弗洛雷斯(Mauricio Flores),一位占主导地位的学生,将参与父母R01赠款支持的研究计划
表征Notch信号在NEPC转分化中的作用。研究,指导和职业
发展计划提出了三个研究目的:1)确定足以支持的器官培养条件
NEPC体外转变; 2)测试Notch信号如何在体外影响NEPC转变; 3)
鉴定在体外影响NEPC转分化的基质癌细胞相互作用。长期目标
这种多样性补充是为了促进弗洛雷斯先生的癌症研究职业发展并改善前列腺
通过推进对谱系可塑性的机械理解作为获得的机制,癌症治疗
治疗性抗性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
DAVID W. GOODRICH的其他基金
YAP1 and RB1 cooperate to regulate lung cancer lineage plasticity and therapeutic resistance
YAP1和RB1合作调节肺癌谱系可塑性和治疗耐药性
- 批准号:1082972410829724
- 财政年份:2022
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
Coordinating and Data Management Center for Acquired Resistance to Therapy Network
获得性治疗耐药网络协调和数据管理中心
- 批准号:1051653710516537
- 财政年份:2022
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
Coordinating and Data Management Center for Acquired Resistance to Therapy Network
获得性治疗耐药网络协调和数据管理中心
- 批准号:1068249510682495
- 财政年份:2022
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
- 批准号:1052412710524127
- 财政年份:2019
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
- 批准号:1075901510759015
- 财政年份:2019
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
- 批准号:1064167210641672
- 财政年份:2019
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
- 批准号:1039753510397535
- 财政年份:2019
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
(PQB5) Does the timing of Pten and Rb1 mutation affect prostate cancer phenotypes
(PQB5) Pten 和 Rb1 突变的时间是否影响前列腺癌表型
- 批准号:85872068587206
- 财政年份:2013
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
(PQB5) Does the timing of Pten and Rb1 mutation affect prostate cancer phenotypes
(PQB5) Pten 和 Rb1 突变的时间是否影响前列腺癌表型
- 批准号:87087958708795
- 财政年份:2013
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
The Role of Thoc1 in Normal Development and Cancer
Thoc1 在正常发育和癌症中的作用
- 批准号:73322857332285
- 财政年份:2007
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
相似国自然基金
雄激素受体调控cIAP/RIPK2/NOD2通路影响结石免疫微环境促进肾结石发生发展的机制研究
- 批准号:82370764
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
PARP1介导DNA损伤修复调控雄激素受体影响前列腺癌放疗敏感性的机制研究
- 批准号:82303674
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
BaP通过激活AhR调控FGF-21和雄激素受体影响非酒精性脂肪肝病的机制研究
- 批准号:82260733
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
胶质瘤干细胞外泌体衍生的circHOMER1靶向雄激素受体影响肿瘤胆固醇代谢的机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
胶质瘤干细胞外泌体衍生的circHOMER1靶向雄激素受体影响肿瘤胆固醇代谢的机制研究
- 批准号:82273281
- 批准年份:2022
- 资助金额:52.00 万元
- 项目类别:面上项目
相似海外基金
A novel targetable mechanism for castration-resistant prostate cancer
去势抵抗性前列腺癌的新型靶向机制
- 批准号:1051328110513281
- 财政年份:2022
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
Interactions of Androgen Production, Uptake and Metabolism on outcome in Castration Resistant Prostate Cancer
雄激素产生、摄取和代谢的相互作用对去势抵抗性前列腺癌预后的影响
- 批准号:1046040010460400
- 财政年份:2021
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
增强雄激素信号抑制剂在前列腺癌中的功效
- 批准号:1065914110659141
- 财政年份:2021
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
增强雄激素信号抑制剂在前列腺癌中的功效
- 批准号:1029478710294787
- 财政年份:2021
- 资助金额:$ 4.86万$ 4.86万
- 项目类别:
Interactions of Androgen Production, Uptake and Metabolism on outcome in Castration Resistant Prostate Cancer
雄激素产生、摄取和代谢的相互作用对去势抵抗性前列腺癌预后的影响
- 批准号:1090811010908110
- 财政年份:2021
- 资助金额:$ 4.86万$ 4.86万
- 项目类别: